Granulate or powder for producing coating or binding agents for medicaments

ABSTRACT

The invention relates to a method for the production of a coating and excipient agent for oral or dermal dosage forms, consisting of (a) 35-98% by weight of a copolymer consisting of radically polymerized C1-C4 esters of acrylic or methacrylic acid and additional (meth)acrylate monomers having functional tertiary ammonium groups and (b) 1-50% by weight of a softener and 1-15% by weight of an emulgator with an HLB value of less than 14, wherein constituents (a), (b) and (c) are mixed with or without adding water and optionally adding a pharmaceutical active substance and other conventional additives and the coating and excipient agent is produced by melting, casting, spreading or spraying. The invention is characterized in that the copolymer (a) is applied in powder form with a mean particle size of 1-40 &amp;mgr;m.

[0001] The invention relates to a powder or granules for the productionof coating agents and binders for pharmaceutical forms.

[0002] Prior Art

[0003] U.S. Pat. No. 4,705,695 describes a process for the coating ofpharmaceutical formulations with an aqueous coating agent comprising awater-soluble (meth)acrylate copolymer having tertiary amino groups, anda water-insoluble, neutral polymer as a binder. The solubility of the(meth)acrylate copolymer consisting, for example, of equal proportionsof methyl methacrylate and dimethylaminoethyl methacrylate, is broughtabout by stirring in in powder form with particle sizes below 0.25 mm inwater with simultaneous addition of an acid. The binder employed is aninsoluble copolymer, e.g. of methyl methacrylate and ethyl acrylate(70:30). The production of the coating solution is relativelycomplicated. Because of the content of acid, the coating has anunpleasant taste. Appropriate films dissolve both in artificial gastricjuice and in water in less than two minutes. WO 00/05307 describes aprocess for the production of a coating agent and binder for oral ordermal pharmaceutical forms consisting of (a) 35-98% by weight of acopolymer, consisting of free radical-polymerizable C1- to C4-esters ofacrylic or methacrylic acid and further (meth)acrylate monomers whichhave functional tertiary amino groups and (b) 1-50% by weight of aplasticizer and 1-15% by weight of an emulsifier having an HLB of atleast 14 where the components (a), (b) and (c) are blended with oneanother with or without addition of water and optionally with additionof a pharmaceutical active compound and further customary additives andthe coating agent and binder is produced by fusing, casting, spreadingor spraying, the copolymer (a) being incorporated in powder form with amean particle size of 1-40 μm.

[0004] A copolymer corresponding to WO 00/05307 of methyl methacrylate,butyl methacrylate, and dimethylamino-ethyl methacrylate in the ratio25:25:50 having a mean particle size of 15 μm is on the market under thename EUDRAGIT® EPO (Registered trademark of Rohm GmbH & Co. KG) and thusprior art.

[0005] The formulation in the defined powder form in combination withplasticizer and emulsifier makes it possible to convert thecorresponding copolymers into stable aqueous solutions or dispersionswithout the addition of acids. There is the advantage that a bitterintrinsic taste of the coating agent which otherwise occurs can beavoided. The coating agents and binders are moreover scarcely soluble inwater, but dissolve rapidly in artificial gastric juice. They aretherefore suitable, in particular, for taste-isolating formulationswhich disintegrate rapidly in the gastric juice.

[0006] A further development of WO 00/05307 has been made known by thepublications of Roth et al. (“Improved Moisture Protection with NewAqueous Aminomethacrylate Copolymer Formulations”, CRS, Annual Meeting2002 in Seoul (Korea) July 2002) and Petereit “new aspects of moistureprotection and insulation of solid dosage forms with EUDRAGIT® EPO” 33thInternational EUDRAGIT® Workshop 2001 (Darmstadt, 27-28 September 2001).

[0007] It is reported that the addition of C12-C18-fatty acids oralcohols brings about moisture protection. The addition of, for example,10% by weight of sodium lauryl sulfate and 15% by weight of stearic acidto EUDRAGIT® EPO in dispersed form is especially recommended.

[0008] Object and Achievement

[0009] The invention originates essentially from the EUDRAGIT® EPOformulations mentioned at the outset with addition of C12-C18-fattyacids or alcohols and emulsifiers such as, for example, sodium laurylsulfate. Coating agents and binders produced therefrom advantageouslyhave only a low water vapor permeability (moisture protection action).The publications of Roth et al. and Petereit recommend the dispersion ofthe individual components present as powders under stirring conditions.The use of the pulverulent components has the disadvantage that anundesirable formation of powder dusts always accompanies it, which as arule is undesirable in the case of the end user. It was thereforeregarded as an object to make available an intermediate which can beprocessed easily and with markedly reduced dust development by the enduser to give a coating agent and binder.

[0010] The object is achieved by a

[0011] process for the production of granules or powder, suitable as acoating agent and binder for oral or dermal pharmaceutical forms, forcosmetics or food supplements, consisting essentially of

[0012] (a) a copolymer, consisting of free radical-polymerized C1- toC4-esters of acrylic or methacrylic acid and further (meth)acrylatemonomers which contain functional tertiary amino groups,

[0013] (b) 3 to 25% by weight, based on (a), of an emulsifier having anHLB of at least 14,

[0014] (c) 5 to 50% by weight, based on (a), of a C₁₂- toC₁₈-monocarboxylic acid or of a C₁₂- to C₁₈-hydroxyl compound,

[0015] where the components (a), (b) and (c) are simultaneously orsuccessively blended or mixed with one another, optionally with additionof a pharmaceutical active compound and/or further customary additives,fused in a heatable mixer, mixed, the melt is cooled and comminuted togive granules or powder.

[0016] Owing to the extrusion process of the components (a), (b) and(c), and optionally additionally added pharmaceutical active compoundsand/or further customary additives, a molecular matrix obviously resultswhich, after comminution, substantially affords dust-free processablepowder or granules. The end user can easily process the granules orpowder further in a customary manner. The powder or granules save theprestocking, weighing and the incorporation of many individualcomponents, since these are already present in the specified amounts.The dust development using the powders or granules according to theinvention is avoided. It is surprising that even copolymers as incomponent (a), which are present in powder form having a mean particlesize of over 40 μm, and which in this form as a rule necessitaterelatively long dispersion times, of, for example, a number of hours,can be converted in this way into a rapidly dispersible form. It is evenmore surprising, however, that using the present invention evengranules, for example, having particle sizes of 0.5-5 mm, can beconverted into a rapidly dispersible form.

[0017] Carrying out the Invention

[0018] Component (a)

[0019] The copolymers (a) consist essentially or completely of freeradical-polymerized C1- to C4-esters of acrylic or methacrylic acid andfurther (meth)acrylate monomers which contain functional tertiary aminogroups.

[0020] Suitable monomers having functional tertiary amino groups arelisted in U.S. Pat. No. 4,705,695, column 3, line 64 to column 4, line13. In particular, dimethylaminoethyl acrylate, 2-dimethylaminopropylacrylate, dimethyl-aminopropyl methacrylate, dimethylaminobenzylacrylate, dimethylaminobenzyl methacrylate,(3-dimethylamino-2,2-dimethly)propyl acrylate,dimethylamino-2,2-dimethly)-propyl methacrylate,(3-diethylamino-2,2-dimethly)-propyl acrylate anddiethylamino-2,2-dimethly)propyl methacrylate may be mentioned.Dimethylaminoethyl methacrylate is particularly preferred.

[0021] The content of the monomers having tertiary amino groups in thecopolymer can advantageously be between 30 and 70% by weight, preferablybetween 40 and 60% by weight. The proportions of the C1- to C4-esters ofacrylic or methacrylic acid is 70-30% by weight. Methyl methacrylate,ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate,butyl acrylate may be mentioned.

[0022] A (meth)acrylate copolymer having tertiary amino groupscorresponding to the component (a) can be built up, for example, from20-30% by weight of methyl methacrylate, 20-30% by weight of butylmethacrylate and 60-40% by weight of dimethylaminoethyl methacrylate.The proportion of component (a) in the formulation is preferably 50-90%by weight.

[0023] The copolymers (a) are obtained in a manner known per se byfree-radical substance, solution, bead or emulsion polymerization. Theyare brought into a form which is miscible dry or in the melt with thecomponents (b) and (c) before processing by means of suitable grinding,drying or spraying processes. In particular, the granule or powder formis suitable for further processing. Suitable implements for this arefamiliar to the person skilled in the art, e.g. die-face pelletizers,strand pelletizers, air jet mills, pinned disk mills, fan mills.Optionally, appropriate sieving steps can be included. A suitable millfor large industrial amounts for the production of powders is, forexample, an opposed jet mill (Multi No. 4200), which is operated atabout 6 bar overpressure. Suitable powders can, for example, meanparticle sizes of 1-40 μm (EUDRAGIT® EPO type) or between 40 μm to 500μm. Granules can, for example, be rounded, lenticular or cylindricalwith particle sizes of 0.5 to 50 mm, preferably 1 to 5 mm (EUDRAGIT® Etype).

[0024] Component (b)

[0025] Emulsifiers or surfactants are surface-active substances havinglyobipolar character, i.e. nonpolar, lipophilic and polar, hydrophiliccenters must be present in their molecule (P.H. List, Arzneiformenlehre[Pharmaceutical form theory], Wissenschaftliche Verlagsgesellschaft mbHStuttgart, 1982, chap. 6.2.). Depending on molecular structure, adistinction is made between ionic and nonionic emulsifiers.

[0026] The HLB is a measure of the hydrophilicity or lipophilicity ofnonionic surfactants introduced in 1950 by Griffin. It can be determinedexperimentally by the phenol titration method according to Marszall; cf.“Parfümerie, Kosmetik” [Perfumery, cosmetics], volume 60, 1979, pp.444-448; further references in Römpp, Chemie-Lexikon [Chemicalencyclopedia], 8th ed. 1983, p. 1750. See furthermore, for example, U.S.Pat. No. 4,795,643 (Seth)).

[0027] An HLB (hydrophilic/lipophilic balance) can only be determinedexactly with nonionic emulsifiers. With anionic emulsifiers, this valuecan be determined arithmetically, but is virtually always above or farabove 14.

[0028] Emulsifiers (b) having an HLB of above 14 are understoodaccording to the invention as meaning hydrophilic, nonionic emulsifiershaving an HLB range of at least 14, and likewise hydrophilic, anionicemulsifiers and their salts which have an arithmetical HLB of above 14.Emulsifiers having HLBs of less than 14, such as, for example, glycerolmonostearate can admittedly additionally also be present, but do notreplace the emulsifiers (b) having HLBs of at least 14.

[0029] Suitable emulsifiers (b) are, for example, sodium lauryl sulfateand sodium cetylstearyl sulfate, sucrose stearate and polysorbate 80.The emulsifiers (b) are present in amounts of 1-25, preferably 5-10, %by weight based on component (a). Of course, the use of emulsifiermixtures is also possible.

[0030] The addition of the emulsifiers (b) to the formulation can beperformed in a known manner, directly, in aqueous solution or afterthermal pretreatment of the mixture.

[0031] Depending on type (lipophilic or hydrophilic) and amount added,the emulsifiers can influence the functionality of the polymer layer.

[0032] Component (c)

[0033] Component (c): 5 to 50, preferably 10 to 20, % by weight, (basedon component (a)), of a C₁₂- to C₁₈-monocarboxylic acid or of a C₁₂- toC₁₋₈-hydroxyl compound. Component (c) is crucial for the surprisinglylow water vapor permeability of the formulations. Unbranched C₁₂- toC₁₈-monocarboxylic acid or a C₁₂- to C₁₈-hydroxyl compounds arepreferred. If appropriate, branched derivatives of the substancesmentioned can also be suitable.

[0034] C₁₂- to C₁₈-monocarboxylic acids are, for example, in particular,lauric acid and myristic acid. Palmitic acid and stearic acid arepreferred.

[0035] C₁₂- to C₁₈-hydroxyl compound, in particular alkanols having aterminal hydroxyl group such as, for example, lauryl alcohol or stearylalcohol.

[0036] Further Additives

[0037] Customary additives are preferably added to the formulationaccording to the invention during the production of the granules orpowders. The additives can also additionally be added to the coatingagent and binder during processing. In principle, of course, allsubstances employed must be toxicologically harmless and in particularbe able to be used in medicaments without risk for patients.

[0038] Amounts employed and use of the customary additives inpharmaceutical coatings or coverings are familiar to the person skilledin the art. Customary additives can be, for example, mold-releaseagents, pigments, stabilizers, antioxidants, pore-forming agents,penetration promoters, lustering agents, aromatic substances orflavorings. They are used as processing aids and should guarantee a safeand reproducible production process and good long-term storage stabilityor they achieve additional advantageous properties in the pharmaceuticalform. They are added to the polymer preparations before processing andcan influence the permeability of the coatings, which can optionally beutilized as an additional control parameter.

[0039] Mold-Release Agents:

[0040] Mold-release agents as a rule have lipophilic properties and as arule are added to the spray suspensions. They prevent agglomeration ofthe cores during the making into a film. Preferably, talc, Mg stearateor Ca stearate, ground silicic acid, kaolin or nonionic emulsifiershaving an HLB of between 3 and 8 are employed. Customary amountsemployed for mold-release agents in the coating agents and bindersaccording to the invention are between 0.5 to 100% by weight based onthe copolymer (a).

[0041] Pigments:

[0042] Pigments incompatible with the coating agent are in particularthose pigments which, when they are added directly to the (meth)acrylatecopolymer dispersion, e.g. by stirring in, in customary use amounts of,for example, 20 to 400% by weight based on the dry weight of the(meth)acrylate copolymer, lead to the destabilization of the dispersion,coagulation, to demixing phenomena or similarly undesirable effects.Furthermore, the pigments to be used are, of course, nontoxic andsuitable for pharmaceutical purposes. For this, for example, also see:Deutsche Forschungs-gemeinschaft [German research association],Farbstoffe für Lebensmittel [Colorants for foodstuffs], Harald BoldtVerlag KG, Boppard (1978); Deutsche Lebensmittel-rundschau 74, No. 4, p.156 (1978); Arzneimittel-farbstoffverordnung [Pharmaceutical colorantsorder] AmFarbV of 08.25.1980.

[0043] Pigments incompatible with the coating agent can be, for example,aluminum oxide pigments. Incompatible pigments are, for example, OrangeYellow, Cochineal Red lake, color pigments based on aluminum oxide orazo dyes, sulfonic acid dyes, Orange Yellow S (E110, C.I. 15985, FD&CYellow 6), indigocarmine (E132, C.I. 73015, FD&C Blue 2), tartrazine (E102, C.I. 19140, FD&C Yellow 5), Ponceau 4R (E 125, C.I. 16255, FD&CCochineal Red A), Quinoline Yellow (E 104, C.I. 47005, FD&C Yellow 10),erythrosine (E 127, C.I. 45430, FD&C Red 3), azorubine (E 122, C.I.14720, FD&C carmoisine), amaranth (E 123, C.I. 16185, FD&C Red 2),Brilliant Acid Green (E 142, C.I. 44090, FD&C Green S).

[0044] The E numbers of the pigments indicated refer to EU numbering.For this see also “Deutsche Forschungs-gemeinschaft, Farbstoffe fürLebensmittel, Harald Boldt Verlag KG, Boppard (1978); DeutscheLebensmittel-rundschau 74, No. 4, p. 156 (1978);Arzneimittel-farbstoffverordnung [Pharmaceutical colorants order]AmFarbV of 08.25.1980. The FD&C numbers refer to the registration inFood, Drugs and Cosmetics by U.S. Food and Drug Administration (FDA)described in: U.S. Food and Drug Administration, Center for Food Safetyand Applied Nutrition, Office of Cosmetics and Colors: Code of FederalRegulations - Title 21 Color Additive Regulations Part 82, Listing ofCertified Provisionally Listed Colors and Specifications (CFR 21 Part82).

[0045] Plasticizers

[0046] Further additives can also be plasticizers. Customary amounts arebetween 0 and 50, preferably 0 to 20, in particular 0 to 10, % byweight. Particularly preferably, however, at most 5% by weight or noplasticizer is contained, since the formulations are frequently alreadyelastic enough due to the presence of the components (c) and additionalplasticizer can lead to undesirable tackiness.

[0047] Depending on type (lipophilic or hydrophilic) and amount added,plasticizers can influence the functionality of the polymer layer. Bymeans of physical interaction with the polymer, plasticizers achieve alowering of the glass transition temperature and promote, depending onthe amount added, making into a film. Suitable substances as a rule havea molecular weight between 100 and 20,000 and contain one or morehydrophilic groups in the molecule, e.g. hydroxyl, ester or aminogroups.

[0048] Examples of suitable plasticizers are alkyl citrates, glycerolesters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitanesters, diethyl sebacate, dibutyl sebacate and polyethylene glycols 200to 12,000. Preferred plasticizers are triethyl citrate (TEC),acetyl-triethyl citrate (ATEC) and dibutyl sebacate (DBS). Esters whichas a rule are liquid at room temperature, such as citrates, phthalates,sebacates or castor oil, are furthermore to be mentioned. Preferably,citric acid esters and sebacic acid esters are used.

[0049] The addition of the plasticizer to the formulation can beperformed in a known manner, directly, in aqueous solution or afterthermal pretreatment of the mixture. Mixtures of plasticizers can alsobe employed.

[0050] Processing to give granules or powders

[0051] The components (a), (b) and (c) are optionally blended or mixedwith one another simultaneously or successively with addition of apharmaceutical active compound and/or further customary additives. Thecomponents are then fused in a heatable mixer, mixed and the melt iscooled and comminuted to give granules or powders.

[0052] It is possible, for example, to dry the components (a), (b) and(c), and the pharmaceutical active compound and/or further customaryadditives optionally present, for example to mix them with one anotherin a gravity mixer or in a mechanical mixer. It is also possible,however, to feed the components (a), (b) and (c), and the pharmaceuticalactive compound and/or further customary additives optionally present,on their own or as a component mixture, directly to a heatable mixer,e.g. an extruder, via continuously operating automatic feeders. It isalso possible to meter the components (b) and (c), and thepharmaceutical active compound and/or further customary additivesoptionally present into the melt of the component (a) on their own or asa component mixture dry or if appropriate in the fused state.

[0053] The mixture is preferably fused in an extruder and extruded bymeans of an extruder, e.g. extruded at temperatures in the range from 80to 160, preferably 100 to 150° C. It can be a single-screw or adouble-screw extruder, at whose end the extrudate emerges, for example,as a melt strand. The extrudate obtained is comminuted to give granulesor powder. This can be carried out, for example, by means of a hot chipgranulator, an extrudate granulator and/or grinding in a mill, e.g. apinned disk mill. The extrudate can, for example, be drawn off via awithdrawal belt and fed to an extrudate granulator, which cuts up thestrand into pieces 1 to 5 mm long. In the case of granules, the meangrain size can be, for example, in the range from 0.5 to 5 mm,preferably 1 to 3 mm. Suitable powder sizes can be in the range from 1to 500 μm, preferably 100 to 500 μm.

[0054] The Further Processing of the Powder or Granules According to theInvention

[0055] The invention accordingly relates to granules or powders whichcan be produced by means of extrusion and subsequent comminution of theextrudate and are suitable as a precursor which is easily dispersible inwater or fusible, or as an intermediate, for a coating agent and binderfor oral or dermal pharmaceutical forms.

[0056] The granules or powders can be processed further at room orelevated temperature with or without addition of water and optionallywith addition of pharmaceutical active compounds and/or furthercustomary additives which are still not contained in a manner known perse by fusing, casting, spreading, spraying or granulating to givecoating agents and binders. In this process, the making into a film ofthe coating agent and binder is a prerequisite for the functional effectin the resulting pharmaceutical forms.

[0057] The conversion of the granules or powders into a dispersion byintroduction into water and stirring at room temperature is preferred.Alternatively, higher shear forces or elevated temperatures, e.g. 50 to70° C., can be used. Under these conditions, the dispersing time can be,for example, 45 to 120 min.

[0058] The solids content of the resulting dispersion is between 5 and30% by weight, preferably between 10 and 20% by weight). The viscosityof the dispersion depends on the concentration of the solid. As a rule,it is under 1 Pa*s.

[0059] Two or more types of granules or powders, which in each casecontain various color pigment, can be processed by means of mixing togive a coating agent and binder. This has the advantage that coloredmixtures can be produced. In this way, color shades can be generatedwhich cannot be produced using individual color pigments.

[0060] The making into a film takes place, independently of theapplication process, by supply of energy. This can take place by meansof convection (heat), radiation (infrared or microwaves) or conduction.Water employed for application as a suspending agent evaporates here, ifappropriate a vacuum can also be applied in order to accelerate theevaporation. The temperature necessary for the making into a filmdepends on the combination of the components employed.

[0061] Further Processing of the Powders or Granules According to theInvention for the Production of Binders:

[0062] Use as binders is carried out, for example, by spraying theaqueous polymer suspension onto active compound-free cores (nonpareils)with simultaneous addition of powdered active compounds or theirmixtures. A further embodiment is the spraying on of the aqueous polymersuspension together with active compounds dissolved or suspendedtherein.

[0063] The granules or powders can also be processed further as bindersby processing by means of wet or melt granulation.

[0064] Further Processing of the Formulation According to the Inventionfor the Production of Coating Agents:

[0065] The granules or powders can be used as moisture-isolating and/oras taste-isolating coating agents.

[0066] Preformed supports for the coatings are capsules, tablets,granules, pellets, crystals of regular or irregular shape. The size ofgranules, pellets or crystals is between 0.01 and 2.5 mm, that oftablets between 2.5 and 30.0 mm. Capsules consist of gelatin, starch orcellulose derivatives.

[0067] Powders and crystals as a rule contain 100% of the biologicallyactive substance. Preformed carriers contain from approximately 0.1 toup to 99% of the biologically active substance or of the pharmaceuticalactive compound, and to 1 to 99.9% by weight of further pharmaceuticalexcipients.

[0068] Customary production processes are direct compression,compression of dry, moist or sintered granules, extrusion and subsequentrounding, wet or dry granulation or direct pelleting (e.g. to plates) orby binding of powders (powder layering) to active compound-free spheres(nonpareils) or active compound-containing particles.

[0069] In addition to the active compound, they can contain furtherpharmaceutical excipients: binders, such as cellulose and itsderivatives, polyvinylpyrrolidone (PVP), humectants, disintegrationpromoters, lubricants, disintegrants, (meth)acrylates, starch and itsderivatives, sugar solubilizers or others.

[0070] Of particular importance is the disintegration time of the cores,which influences the release of the active compound. Today, shorterdisintegration times of under 5, or under 10, min are strived for in thedisintegration test according to Ph. Eur. Longer disintegration timesare problematic because additional coatings further delay the release ofthe active compound and can put the therapeutic effect in question.Today, a disintegration time of 30 min is regarded as a threshold value.Testing is carried out in water and artificial gastric juice (0.1 NHCl). The cores employed are homogeneous or have a laminated structure.If engravings are inlaid into the surfaces, these should be covered bycoatings if possible but only slightly filled in. The layer thickness ofthe polymer powder employed according to the invention varies greatlyand depends on the processing procedure or the amount of additives. Itis between 1 and 100 μm, preferably between 10 and 50 μm. On customarytablets, one polymer application corresponds to from 0.5 to 5% byweight.

[0071] Coated microparticles can be compressed to give disintegratingtablets according to K. Lehmann et al., Drugs made in Germany 37, 2,53-60 (1994) and T.E. Beckert et al, International Journal ofPharmaceutics 143, (1996), 13-23, without significant influence on thefunction of the polymer.

[0072] The function of the polymer layer made into a film in the finalpharmaceutical form can be varied:

[0073] Protection from harmful environmental influences due to moisture,gases, light etc.

[0074] Odor or taste isolation,

[0075] marking by color

[0076] mechanical stabilization

[0077] isolation of incompatible ingredients

[0078] avoidance of adherence to the mucous membranes.

[0079] temporarily delayed release of active compound

[0080] pH-controlled release of active compound

[0081] isolation of cores from further coatings

[0082] The low viscosity of the polymer mixture in aqueous dispersionsis advantageous even at high solids contents of up to 30%, sinceengravings on the surface of tablets are reproduced in detail.

[0083] The good protective and isolating action of the polymer mixtureaccording to the invention with, at the same time, a small influence ontablet disintegration is particularly advantageous. Even at low polymerapplications of 1% by weight, a taste isolation of more than 30 sec isalready achieved. Thicker coatings with a copolymer of methylmethacrylate, butyl methacrylate and dimethylaminoethyl methacrylate inthe ratio 25:25:50 (EUDRAGIT® E or EUDRAGIT® EPO) improve the tasteconcealment, but without prolonging the disintegration time in 0.1N HCl.The reliable covering of colored cores by coatings having a high pigmentcontent is likewise advantageous. One particular embodiment is theembedding of a second active compound in the coating on an activecompound-containing core.

[0084] Application to the Formulation According to the Invention forProduction on Supports

[0085] The formulation according to the invention can be applied inpowder form, as a melt or in aqueous suspension by means of granulation,casting, spreading or by means of spray application. Water is used heremainly as a vehicle in order to apply thin coatings uniformly tospherical cores, e.g. by spraying. Spreading processes are moreoveremployed for coatings. The process employed depends mainly on thecarrier chosen. Dry powders are applied by spreading or dusting, ifappropriate also using electrostatic forces. The making into a film canbe carried out by action of heat. For carrying out it is crucial herethat uniform, continuous layers result.

[0086] For application processes according to the prior art see, forexample, Bauer, Lehmann, Osterwald, Rothgang, “Überzogene Arzneiformen”[Coated pharmaceutical forms] Wissenschaftliche Verlagsgesellschaft mbHStuttgart, chap. 7, pp. 165-196.

[0087] Properties relevant for application, tests required andspecifications are listed in pharmacopeia.

[0088] Details can be taken from the customary textbooks, e.g.:

[0089] Voigt, R. (1984): Lehrbuch der pharmazeutischen Technologie[Textbook of pharmaceutical technology]; Verlag Chemie Weinheim -Beerfield Beach/Fla. -Basle.

[0090] Sucker, H., Fuchs, P., Speiser, P.: Pharmazeutische Technologie[Pharmaceutical technology]; Georg Thieme Verlag Stuttgart (1991), inparticular chapters 15 and 16, pp. 626-642.

[0091] Gennaro, A.R. (Editor), Remington's Pharmaceutical Sciences, MackPublishing Co., Easton Pa. (1985), Chapter 88, pp. 1567-1573.

[0092] List, P. H. (1982): Arzneiformenlehre [Pharmaceutical formtheory], Wissenschaftliche Verlags-gesellschaft mbH, Stuttgart.

[0093] Water Vapor Permeability

[0094] While coating agents and binders according to Wo 00/05307 havewater vapor permeabilities measured according to DIN 53 122 in the rangeof 400 (g/m²/d) or above, the water vapor permeabilities of the coatingagents and binders produced from the powders or granules according tothe invention are at most 350 (g/m²/d), preferably at most 300 (g/m²/d),particularly preferably at most 200 (g/m²/d). In particular, the powdersor granules according to the invention can in many cases also beprocessed further with extensive or complete relinquishment of customaryplasticizers. This is advantageous, since it is always attempted to keepthe number of components in pharmaceutical formulations low.

[0095] Biologically Active Substances:

[0096] The pharmaceuticals employed within the meaning of the inventionare intended to be used on or in the human or animal body in order

[0097] 1. to cure, to alleviate, to prevent or to recognize diseases,illnesses, bodily defects or pathological symptoms.

[0098] 2. to allow the condition, the state or the functions of the bodyor mental states to be recognized.

[0099] 3. to replace active compounds or body fluids produced by thehuman or animal body.

[0100] 4. to ward off, to eliminate or to render harmless pathogens,parasites or exogenous substances or

[0101] 5. to influence the condition, the state or the functions of thebody or mental states.

[0102] Customary pharmaceuticals can be taken from the reference works,such as, for example, the Rote Liste or the Merck index.

[0103] The formulation according to the invention is suitable for theadministration of fundamentally any desired pharmaceutical activecompounds, which can preferably be administered in isolated or protectedform, such as antidepressants, beta-receptor blockers, anti-diabetics,analgesics, antiinflammatories, antirheumatics, antihypotensives,antihypertensives, psychopharmaceuticals, tranquillizers, antiemetics,muscle relaxants, glucocorticoids, agents for the treatment ofulcerative colitis or Crohn's disease, antiallergics, antibiotics,antiepileptics, anti-coagulants, antimycotics, antitussives,arteriosclerosis agents, diuretics, enzymes, enzyme inhibitors, goutagents, hormones and their inhibitors, cardiac glycosides,immunotherapeutics and cytokines, laxatives, hypolipidemics,gastrointestinal therapeutics, migraine agents, mineral preparations,otologicals, Parkinson agents, thyroid therapeutics, spasmolytics,platelet aggregation inhibitors, vitamins, cytostatics and metastasisinhibitors, phytopharmaceuticals, chemotherapeutics and amino acids.

[0104] Examples of suitable active compounds are acarbose, nonsteroidalantirheumatics, cardiac glycosides, acetylsalicylic acid, virustatics,aclarubicin, acyclovir, cisplatin, actinomycin, alpha- andbeta-sympathomimetics, (allopurinol, alosetrone, alprostadil,prostaglandins, amantadine, ambroxole, amlodipine, methotrexate,S-aminosalicylic acid, amitriptyline, amlodipine, amoxicillin,anastrozole, atenolol, atorvastatin, azathioprine, balsalazide,beclomethasone, betahistine, bezafibrate, bicalutamide, diazepam anddiazepam derivatives, budesonide, bufexamac, buprenorphine, methadone,calcium salts, potassium salts, magnesium salts, candesartan,carbamazepine, captopril, cefalosporins, celetoxib, cetirizine,chenodeoxycholic acid, ursodeoxycholic acid, theophylline andtheophylline derivatives, trypsins, cimetidine, clarithromycin,clavulanic acid, clindamycin, clobutinol, clonidine, cotrimoxazole,codeine, caffeine, vitamin D and derivatives of vitamin D,colestyramine, cromoglicic acid, coumarin and coumarin derivatives,cysteine, cytarabine, cyclophosphamide, ciclosporin, cyproterone,cytarabine, dapiprazole, desogestrel, desonide, dihydralazine,diltiazem, ergot alkaloids, dimenhydrinate, dimethyl sulfoxide,dimeticone, dipyridamoi, domperidone and domperidan derivatives,donepzil, dopamine, doxazosine, doxorubizin, doxylamine, dapiprazole,benzodiazepines, diclofenac, glycoside antibiotics, desipramine,econazole, ACE inhibitors, enalapril, ephedrine, epinephrine, epoetinand epoetin derivatives, morphinans, calcium antagonists, irinotecan,modafinil, orlistate, peptide antibiotics, phenyloin, riluzoles,risedronate, sildenafil, topiramate, macrolide antibiotics,esomeprazole, estrogen and estrogen derivatives, gestagen and gestagenderivatives, testosterone and testosterone derivatives, androgen andandrogen derivatives, ethenzamide, etofenamate, etofibrate, fenofibrate,etofylline, etoposide, famciclovir, famotidine, felodipine, fenofibrate,fentanyl, fenticonazole, gyrase inhibitors, fluconazole, fludarabine,flunarizine, fluorouracil, fluoxetin, flurbiprofen, ibuprofen,flutamide, fluvastatin, follitropin, formoterol, fosfomicin, furosemide,fusidic acid, galantamine, gallopamil, ganciclovir, gemfibrozil,gentamicin, ginkgo, St John's wort, glibenclamide, urea derivatives asoral antidiabetics, glucagon, glucosamine and glucosamine derivatives,glutathione, glycerol and glycerol derivatives, hypothalamus hormones,goserelin, gyrase inhibitors, guanethidine, halofantrin, haloperidol,heparin and heparin derivatives, hyaluronic acid, hydralazine,hydrochlorothiazide and hydrochloro-thiazide derivatives, salicylates,hydroxyzine, idarubicin, ifosfamide, imipramine, indometacin,indoramine, insulin, interferon, iodine und iodine derivatives,isoconazole, isoprenaline, glucitol and glucitol derivatives,itraconazole, ketoconazole, ketoprofen, ketotifen, lacidipine,lansoprazole, levodopa, levomethadone, thyroid hormones, lipoic acid andlipoic acid derivatives, lisinopril, lisuride, lofepramine, lomustine,loperamide, loratadine, maprotiline, mebendazole, mebeverine, meclozine,mefenamic acid, mefloquin, meloxicam, mepindolol, meprobamate,meropenem, mesalazine, mesuximide, metamizole, metformin, methotrexate,methylphenidate, methylprednisolone, metixen, metoclopramide,metoprolol, metronidazole, mianserine, miconazole, minocycline,minoxidil, misoprostol, mitomycin, mizolastine, moexipril, morphine andmorphine derivatives, evening primrose, nalbuphine, naloxone, tilidine,naproxen, narcotine, natamycin, neostigmine, nicergoline, nicethamide,nifedipine, niflumic acid, nimodipine, nimorazole, nimustine,nisoldipine, adrenalin and adrenalin derivatives, norfloxacin, novaminesulfone, noscapine, nystatin, ofloxacin, olanzapine, olsalazine,omeprazole, omoconazole, ondansetrone, orlistate, oseltamivir,oxaceprol, oxacillin, oxiconazole, oxymetazoline, pantoprazole,paracetamol, paroxetin, penciclovir, oral penicillins, pentazocine,pentifylline, pentoxifylline, perphenazine, pethidine, plant extracts,phenazone, pheniramine, barbituric acid derivatives, phenylbutazone,phenyloin, pimozide, pindolol, piperazine, piracetam, pirenzepine,piribedil, piroxicam, pramipexol, pravastatin, prazosine, procaine,promazine, propiverine, propranolol, propyphenazone, prostaglandins,protionamide, proxyphylline, quetiapin, quinapril, quinaprilate,ramipril, ranitidine, reproterol, reserpine, ribavirin, rifampicin,risperidone, ritonavir, ropinirol, rosiglitazone, roxatidine,roxithromycin, ruscogenin, rutoside and rutoside derivatives, sabadilla,salbutamol, salmeterol, scopolamine, selegiline, sertaconazole,sertindole, sertralion, sildenafil, silicates, simvastatin, sitosterol,sotalol, spaglumic acid, sparfloxacin, spectinomycin, spiramycin,spirapril, spironolactone, stavudine, streptomycin, sucralfate,sufentanil, sulbactam, sulfonamides, sulfasalazine, sulpiride,sultamicillin, sultiam, sumatriptan, suxamethonium chloride, tacrin,tacrolimus, tadalafil, taliolol, tamoxifen, taurolidine, tazarotene,tegaserod, temazepam, teniposide, tenoxicam, terazosine, terbinafine,terbutaline, terfenadine, terlipressin, tertatolol, tetracyclines,tetryzoline, theobromine, theophylline, butizine, thiamazole,phenothiazines, thiotepa, tiagabin, tiapride, propionic acidderivatives, ticlopidine, timolol, tinidazole, tioconazole, tioguanine,tioxolone, tiropramide, tizanidine, tolazoline, tolbutamide, tolcapone,tolnaftate, tolperisone, topotecan, torasemide, anti6strogens, tramadol,tramazoline, trandolapril, tranylcypromine, trapidil, trazodone,triamcinolone and triamcinolone derivatives, triamterene, trifluperidol,trifluridine, trimethoprim, trimipramine, tripelennamine, triprolidine,trifosfamide, tromantadine, trometamol, tropalpine, troxerutin,tulobuterol, tyramine, tyrothricin, urapidil, ursodeoxycholic acid,chenodeoxycholic acid, valacyclovir, valdecoxib, valproic acid,vancomycin, vardenafil, vecuronium chloride, venlafaxin, verapamil,vidarabine, vigabatrine, viloxazine, vinblastine, vincamine,vincristine, vindesine, vinorelbine, vinpocetin, viquidil, warfarin,xantinol nicotinate, xipamide, zafirlukast, zalcitabin, zanamivir,zidovudine, zolmitriptan, zolpidem, zoplicon, zotepine and the like.

[0105] The active compounds can, if desired, also be used in the form oftheir pharmaceutically acceptable salts or derivatives, and in the caseof chiral active compounds both optically active isomers and racematesor diastereoisomer mixtures can be employed. If desired, thecompositions according to the invention can also contain two or morepharmaceutical active compounds.

[0106] Examples of particularly preferred active compounds areacetylsalicylic acid, carbenoxolone, cefalotin, epinefrine, imipramine,potassium iodide, ketoprofen, levodopa, nitrazepam, nitroprusside,oxitetracycline HCl, promethazine, omeprazole or other benzimidazolederivatives and streptomycin.

[0107] Particularly preferred are moisture-sensitive pharmaceuticalactive compounds from the active compounds classes of the analgesics,antirheumatics, active compounds for the treatment of gastric ulcers,antibiotics, antihypotensives, antidepressants, thyroid therapeutics,Anti Parkinson active compounds, anxiolytics, peptides,phospohordiesterase inhibitors, proteins, cardiovascular agents orneuroleptics or their salts is present.

[0108] Moisture-sensitive pharmaceutical active compounds are, forexample, acetylsalicylic acid, carbenoxolone, cefalotin, epinefrine,imipramine, potassium iodide, ketoprofen, levodopa, nitrazepam,nitroprusside, oxitetracycline HCl, promethazine, omeprazole or otherbenzimidazole derivatives, ranitidine or streptomycin or their salts.

[0109] Administration Forms:

[0110] In principle, the pharmaceutical forms described can be useddirectly by means of oral administration. The granules, pellets, orparticles produced according to the invention can be filled into gelatincapsules, sachets or into suitable multidose containers having ametering device. They are taken in solid form or suspended in liquids.By means of compression from, optionally after admixture of furtherexcipients, tablets which disintegrate after taking and which usuallyrelease coated subunits are obtained. Likewise conceivable is theembedding of agglomerates in polyethylene glycol or lipids for theproduction of suppositories or vaginal pharmaceutical forms. Coatedtablets are packed in blister packs or multidose containers and removedby the patient directly before taking.

[0111] Classes of active compounds and substances which often canproduce a bitter taste and can advantageously be formulated using thecoating agents and binders according to the invention are, for example:

[0112] Analgesics and Antirheumatics:

[0113] paracetamol, diclofenac, aceclofenac, ibuprofen, ketoprofen,flubiprofen, levacetylmethadol, oxycodone

[0114] Psychopharmaceuticals:

[0115] prometazine, donepezil, modafinil, nefazodone, reboxetin,sertindole, sertralin

[0116] Antibiotics:

[0117] erythromicyn, roxithromycin, clarithromycin, grepafloxacin,ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin, nevirapine

[0118] Beta-blockers

[0119] propanolol, metoprolol, bisoprolol, nebivolol

[0120] Antidiabetics:

[0121] metformine, miglitol, repaglinide

[0122] H1 Antihistaminics:

[0123] diphenhydramine, fexofenadine, mizolastine

[0124] H2 Antihistaminics

[0125] cimetidine, nizatidine, ticlopidine, cetridine, ranitidine,

[0126] Vitamins: thiamine nitrate; Others: quinidine sulfate,amiloprilose HCl, pseudoephedrine HCl, sildenafil, topiramate,granisetrone, rebamipides, quinine HCl.

EXAMPLES

[0127] EUDRAGIT® E 100: copolymer of methyl methacrylate, butylmethacrylate, and dimethylaminoethyl methacrylate in the ratio 25:25:

[0128] P=parts by weight=% by weight

Example 1

[0129] Production of colorless granules which can be rapidly dispersed.

[0130] 15 parts (P) of stearic acid are mixed with 7 P of sodium laurylsulfate in a suitable mixer and subsequently extruded with 100 P ofEUDRAGIT® E 100 in a synchronous 18 mm double screw extruder, whosescrews are provided with compounding elements, at temperatures between105 to 140° C. with a throughput of about 1.6 kg/h. The extrudate isdrawn off via a withdrawal belt and fed to an extrudate granulator,which comminutes the extrudate into pieces about 3.05 mm (0.12 inch)long. The mean diameter of the granule grains obtained is 2 mm and isdependent on the withdrawal rate of the extrudate.

[0131] 15 P of the granules thus obtained can be dispersed in 100 P ofpurified water within 60 min at 63° C. by means of a magnetic stirrer.The film cast from this dispersion is homogeneous.

Example 2

[0132] Production of yellow granules which can be rapidly dispersed.

[0133] 15 P of stearic acid are mixed with 10 P of sodium lauryl sulfateand 15 P of SICOVIT Yellow 10 (E 172) in a suitable mixer andsubsequently extruded with 100 P of EUDRAGIT® E 100 in a synchronous 18mm double screw extruder, whose screws are provided with compoundingelements, at temperatures between 105 to 140° C. with a throughput ofabout 1.6 kg/h. The extrudate is drawn off via a withdrawal belt and fedto an extrudate granulator, which comminutes the extrudate into piecesabout 3.05 mm (0.12 inch) long. The mean diameter of the granule grainsobtained is 2 mm and is dependent on the withdrawal rate of theextrudate.

[0134] 15 P of the granules thus obtained can be dispersed in 100 P ofpurified water within 60 min at 63° C. by means of a magnetic stirrer.The film cast from this dispersion is homogeneous.

Example 3

[0135] Production of blue granules which can be rapidly dispersed.

[0136] 15 P of stearic acid are mixed with 10 P of sodium lauryl sulfateand 15 P of SICOPHARM indigotin lake (E 132) in a suitable mixer andsubsequently extruded with 100 P of EUDRAGIT® E 100 in a synchronous 18mm double screw extruder, whose screws are provided with compoundingelements, at temperatures between 105 to 140° C. with a throughput ofabout 1.6 kg/h. The extrudate is drawn off via a withdrawal belt and fedto an extrudate granulator, which comminutes the extrudate into piecesabout 3.05 mm (0.12 inch) long. The mean diameter of the granule grainsobtained is 2 mm and is dependent on the withdrawal rate of theextrudate.

[0137] 15 P of the granules thus obtained can be dispersed in 100 P ofpurified water within 60 min at 63° C. by means of a magnetic stirrer.The film cast from this dispersion is homogeneous.

Example 4

[0138] Production of taste-isolated quinidine sulfate tablets For theproduction of the spray dispersion, 532 g of completely demineralizedwater warmed to 63° C. are introduced. 111.72 g of the granulesdescribed in example 2 are added to the water and dispersed withstirring for about 60 min. 11.17 g of talc are added to the dispersionas a mold release agent. Using the spray dispersion obtained, 3000 g ofquinidine sulfate cores (Ø 10 mm) are sprayed with a supply of warm air.The product temperature is between 25 and 33° C. The coated cores weresubsequently dried on racks at 40° C. for two hours. The film coatingobtained is uniform (and) of good covering power and shows itsimperviousness by a taste isolation of greater than 30 min.

Example 5

[0139] Production of a dispersion from two different colored granules

[0140] 7.5 P each of the granules described in examples 2 and 3 aredispersed in 100 P of purified water at 63° C. for about 60 min. Thedispersion thus obtained has a homogeneous green color. The film castfrom this dispersion is, after drying, likewise satisfying with ahomogeneous color shade.

1. A process for preparation of a coating and binding agent for oral or dermal pharmaceutical forms comprising (a) 35 to 98 wt % of a copolymer comprising radical-polymerized C1 to C4 esters of acrylic or methacrylic acid and further (meth)acrylate monomers containing functional tertiary ammonium groups and (b) 1 to 50 wt % of a plasticizer as well as (c) 1 to 15 wt % of an emulsifier with an HLB value of at least 14, wherein the components (a), (b) and (c) are intermixed with each other with or without addition of water and possibly with addition of a pharmaceutical active principle and further common fillers, and the coating and binding agent is prepared by melting, casting, doctoring or spraying, characterized in that the copolymer (a) is introduced in powder form with a mean particle size of 1 to 40 μm.
 2. A process according to claim 1, characterized in that a release agent is applied in concentrated form as the outer layer on the coating and binding agent.
 3. A process according to claim 1, characterized in that a pigment is applied in concentrated form as the outer layer on the coating and binding agent.
 4. A coating and binding agent that can be prepared by the process according to claim
 1. 5. A copolymer comprising radical-polymerized C1 to C4 esters of acrylic or methacrylic acid and further (meth)acrylate monomers containing functional tertiary ammonium groups, characterized in that it exists in the form of powder with a mean particle size of 1 to 40 μm.
 6. A copolymer according to claim 5, characterized in that it comprises 20 to 30 wt % of methyl methacrylate, 20 to 30 wt % of butyl methacrylate and 60 to 40 wt % of dimethylaminoethyl methacrylate.
 7. The use of the coating and binding agent according to claim 4 as a taste-masking coating for pharmaceutical compositions containing active principles.
 8. The use of the coating and binding agent according to claim 4 as a moisture-insulating coating for pharmaceutical compositions containing active principles.
 9. The use of the coating and binding agent according to claim 4 in a transdermal therapy system. 